1. Field of the Invention
The present invention relates to ophthalmic pharmaceutical formulations. More particularly, the present invention relates to therapeutic and prophylactic use of 11-(3-dimethylamino-propylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid for treating and/or preventing cytokine release from human ocular cells and resulting ocular neovascularization or non-allergic inflammatory conditions.
2. Description of the Related Art
As taught in U.S. Pat. Nos. 4,871,865 and 4,923,892, both assigned to Burroughs Wellcome Co. ("the Burroughs Wellcome Patents"), certain carboxylic acid derivatives of doxepin, including 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepine-2-carboxyli c acid and 11-(3-dimethylamino-propylidene)-6,11-dihydrodibenz[b,e]oxepine-2(E)-acryl ic acid, have antihistaminic and antiasthmatic activity. These two patents classify the carboxylic acid derivatives of doxepin as mast cell stabilizers with antihistaminic action because they are believed to inhibit the release of autacoids (i.e., histamine, serotonin, and the like) from mast cells and to inhibit directly histamine's effects on target tissues. The Burroughs Wellcome Patents teach various pharmaceutical formulations containing the carboxylic acid derivatives of doxepin; Example 8 (I) in both of the patents discloses an ophthalmic solution formulation.
U.S. Pat. No. 5,116,863, assigned to Kyowa Hakko Kogyo Co., Ltd., ("the Kyowa patent"), teaches that acetic acid derivatives of doxepin, including Z-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, have anti-allergic and anti-inflammatory activity. The anti-inflammatory activity is attributable to prostaglandin biosynthesis inhibiting activity (see Col. 28, lines 51-57). The doxepin derivatives disclosed by the Kyowa patent are represented by Compound (I): ##STR1##
Compounds where X represents .dbd.N--, .dbd.CH-- or --CH.sub.2 -- are described as having strong antiallergic activity, whereas compounds where X represents .dbd.N-- are described as having strong antiinflammatory activity (see Col. 24, lines 20-57). Thus, for anti-inflammatory applications, the Kyowa patent suggests doxepin derivatives of Compound (I) where X is .dbd.N--.
The Kyowa patent demonstrates anti-allergic activity and anti-inflammatory activity in Wistar male rats. Medicament forms taught by the Kyowa patent for the acetic acid derivatives of doxepin include a wide range of acceptable carriers; however, only oral and injection administration forms are mentioned. In the treatment of allergic eye disease, such as allergic conjunctivitis, such administration methods require large doses of medicine.
U.S. Pat. No. 5,641,805 discloses topical ophthalmic formulations containing 11-(3-dimethylamino-propylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid for treating allergic eye diseases.